János Matkó Ph.D., D.Sc.
- MSc: Chemistry, 1976, Kossuth Lajos University, Debrecen.
- Ph.D. Biophysics, H.A.S. /University of Debrecen, 1984;
- D.Sc. (Biology): Hungarian Academy of Sciences, Budapest, 1997.
- Postdoc: Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany (1984,1986); State University of New York, Syracuse, USA (1988); The Johns Hopkins University, Baltimore, USA (1989-1991); Visiting professor: JHU, Baltimore, USA (1994-1997, 1 month/year); MPI, Göttingen, Germany, 1999 (1 month). Széchenyi Professor Scholarship: 1999-2002.
- Present position: Professor, Eötvös Lorand University, Institute of Biology, Department of Immunology; Head of "Membrane and Cell Communication” research laboratory.
Our earlier studies together with many others have shown that the plasma membrane of vertebrate cells is highly compartmented. This is due on one hand to the lipid raft membrane microdomains, and on the other hand to the dynamic coupling between the plasma membrane and cortical cytoskeleton. The exact properties of the membrane rafts, however, still remained partly controversial and unresolved. It is generally accepted that the sphingolipids/gangliosides may spontaneously segregate within the fluid bilayer and these clusters are further stabilized by cholesterol. This may end in formation of small, submicrometer size unstable domains, which may grow and expand to large scale signaling domains upon external stimuli received by the cell. The signaling rafts then may form larger, membrane attached complex units, such as “signalosomes” [Eggeling et al., Nature 2009. 457: 1159; Lingwood D, Simons K., Science 2010. 327: 46].
The mechanism and regulation of lipid raft formation still remained unclear, such as their functional role in the normal and pathological immune functions of lymphocytes. To investigate submicron organization levels of lipid microdomains we have developed/adopted several physical techniques for cellular systems, like fluorescence resonance energy transfer (FRET) analysis; flow cytometric differential detergent resistance analysis (FCDR); or the differential-polarization laser scanning confocal microscopy (DP-LSM) [Gombos et al, Cytometry 2004. 61:117; Bacsó et al, Cytometry 2004. 61:105; Szöllősi et al, Methods in Cell Biol. 2004. 75: 105-152.; Szentesi et al, Cytometry 2005. 67A: 119; Gombos et al, Cytometry 2008. 73: 220; Kiss et al, Cytometry 2008. 73: 599].
Currently our group is interested in revealing the factors controlling lipid raft organization in lymphocytes and phagocytes. The immune-regulatory role of steroid lipids (cholesterol and estradiols) in normal and pathological lymphocyte function is also in the focus of our research. Recently we prepared two monoclonal, IgG3-type cholesterol-specific antibodies [Biró et al, J Lipid Res 2007. 48: 19-29]. These mAbs proved to be useful as markers of membrane cholesterol in cells. In addition they were able to block in vitro HIV-1 infection and production of human macrophages and T cells [Beck et al, J Lipid Res 2010. 51:286-96] and to promote macrophage phagocytosis and T cell activation through modulation of antigen presentation [Izsépi et al, Immunol Lett 2012. 143:106-115]. The lipid rafts can also be specific targets of various microbes [Phogat et al, J Intern Med 2007:262, 26], especially if the receptors recognizing surface molecules of the microbes are raft-localized (e.g. HIV, influenza, measle viruses). This raises the possibility of inhibiting the infection by modulation of lipid rafts on target cells. The mechanism of modulatory action of our anti-cholesterol mAbs and the estradiol steroid lipids are currently in the focus of our investigations in the lab.
Communication of the immune cells can be realized in various forms (direct and indirect) and levels. A direct communication is the immunological synapse (IS). The contact structures often form in immune organs (mainly in lymph nodes) between antigen presenting cells (DCs, B cells, macrophages) and Th and Tc lymphocytes or between NK cells and their targets. The IS can be considered as an essential platform of T and NK cell activation [Manz BN, Groves JT: Nat Rev Mol Cell Biol. 2010. 11:342; Valitutti S, Dupré L: Curr Top Microbiol Immunol. 2010. 340:209]. Another new form of long range (up to 100 micrometer distance) direct coupling between immune cells are the so called “membrane nanotubes”. Such nanotubes can form between lymphocytes (B and T cells), between macrophages or dendritic cells, as well as between NK cells and their target cells [Önfelt et al: Science STKE 2005; Davis DM: Nat. Rev. Immunol. 2009. 9:543; Davis DM, Sowinski S: Nat. Rev. Mol. Cell. Biol. 2008. 9:431]. They show various morphologies and transport of molecules or even vesicles along the tube from one cell to another was also reported. Mechanistic details and regulatory factors of membrane nanotube formation are, however, very poorly understood, yet. Our lab is currently investigating the regulation of nanotube formation, the role of lipid rafts in it and the intercellular transport, as well as the contribution of myosin motor proteins to the growth and function of nanotube networks in lymphoid cells.
Membrane nanotube network between mature murine B cells (A) and between dividing B cells (B). (green: cholera toxinB-A488; red: CTXB-A647) (Izsépi et al, MAF12 Conference, 2011, Strasbourg, France)
- Investigation of the composition and role of membrane lipid rafts in the differentiation/polarization of naive T lymphocytes and in the activation of T lymphocytes derived from autoimmune diseases (SLE,RA). Development of an early diagnostic procedure using differential raft lipid composition of lymphocytes, as marker for these diseases.
- The estrogen steroid sex hormone proved to be a risk factor in women for susceptibility to certain autoimmune diseases (e.g. Systemic Lupus Erythematosus, SLE; or Rheumatoid Arthritis, RA) according to recent statistical data. Since both cholesterol and estradiols can control the stability of membrane microdomains (rafts), they can potentially influence signal transduction across them. Our basic goal is to identify the membrane estrogen receptors on lymphocytes and to reveal how the rapid non-genomic estrogen effects influence lymphocyte function (activation, proliferation) in health and disease.
- Investigation of the molecular mechanism of action of the new anti-cholesterol IgG mAb (AC8) in respect of its inhibitory action on HIV-1 infection in in vitro cellular models, using recombinant viral coat proteins and their nanobead conjugates. We hope that the results will help to design mAb tandem construction enable for targeting cells.
- Investigation of the mechanistic details and regulatory factors of membrane nanotube growth in B and T lymphocytes. The role of lipid rafts and myosin motor proteins in the nanotube growth/networking and matter transport along them will also be studied.
- Tissue culture, immunobiochemical methods, protein chemistry; molecular biological methods, signal transduction analysis
- Confocal fluorescence- and video-microscopy, FRET, FRAP (Olympus Fluoview 500 CLSM)
- Multiparameter flow cytometric analysis and cell sorting (Becton Dickinson FACSCalibur; BD FACS Aria III*).
* The lab is an open cell analysis & sorting service unit to interested companies and academic sites (under supervision of the Faculty of Science of ELU)
- TÁMOP 4.2.1./B-09/1/KMR-2010-0003 grant (National Development Agency, NFÜ), with partial support of EU Social Fund. (purchasing FACS Aria III flow cytometer, 100 mHUF, 2010)
- OTKA (National Science Fund)-NFÜ CK 80935 grant (48 mHUF, 2010-2013)
- OTKA (National Science Fund) K 104971 grant (39 mHUF, 2013-2016)
Links for all publications: MTMT
- Vereb G, Matkó J, Vámosi G, et al: Cholesterol-dependent clustering of IL-2Ra and its colocalization with HLA and CD48 on T lymphoma cells suggest their functional association with lipid rafts. Proc.Natl.Acad.Sci. USA, 2000. 97, 6013-6018
- Matkó J, Bodnár A, Vereb G, et al: GPI-microdomains (membrane rafts) and signaling of the multichain interleukin-2 receptor in human lymphoma/leukemia T cell lines. Eur. J. Biochem., 2002. 269,1199-1208.
- Vereb G, Szöllősi J, Matkó J, et al: Dynamic, yet structured: The cell membrane three decades after the Singer-Nicolson membrane model. Proc. Natl. Acad. Sci. USA 2003. 100, 8053-8058.
- Matkó J: K+-channels and T-cell synapses: the molecular background for efficient immunomodulation is shaping up. Trends in Pharmacol. Sci. 2003. 24, 385-389.
- Gombos I, Detre C, Vámosi G, Matkó J: Rafting MHC-II domains in the APC (presynaptic) plasma membrane and the thresholds for T-cell activation and immunological synapse formation. Immunol. Letters 2004. 92, 117-124.
- Gombos I, Bacsó Zs, Detre C, Nagy H, Goda K, Andrásfalvy M, Szabó G, Matkó J: Cholesterol-sensitivity of detergent resistance: A rapid flow cytometric test for detecting constitutive or induced raft association of membrane proteins. Cytometry 2004. 61, 117-126
- Matkó J, Szöllősi J: Regulatory Apects of Membrane Microdomain (Raft) Dynamics in Live Cells: A Biophysical Approach. Chapter 2. in: "Membrane Microdomain Signaling: Lipid Rafts in Biology and Medicine" (ed. by M. Mattson), pp.15-46, Humana Press, 2004.
- Detre C, Kiss E, Varga Z, Ludányi K, Pászty K, Enyedi Á, Kövesdi D, Panyi G, Rajnavölgyi É, Matkó J: Death or survival: Membrane ceramide controls the fate and activation of antigen-specific T cells depending on signal strength and duration. Cellular Signalling 2006. 18:294-306.
- Biró A, Cervenak L, Balogh A, et al: Novel anti-cholesterol monoclonal IgG antibodies as probes and potential modulators of membrane raft-dependent immune functions. Journal of Lipid Research 2007. 48:19-29.
- Gombos I, Steinbach G, Pomozi I, Balogh A, Vámosi Gy, Gansen, A, László G, Garab Gy, Matkó J: Some new faces of membrane microdomains: A complex confocal fluorescence, differential polarization and FCS imaging study on live immune cells. Cytometry A 2008. 73: 220-229.
- Kiss E, Nagy P, Balogh A, Szöllősi J, Matkó J: Cytometry of raft and caveola microdomains: from flow and imaging techniques to High Throughput Screening assays. Cytometry A 2008. 73: 599-614.
- Beck Z, Balogh A, Kis A, Izsépi E, Bíró A, László G, Cervenak L, Liliom K, Mocsár G, Vámosi G, Füst G, Matko J: New cholesterol-specific antibodies remodel HIV-1 target cells' surface and inhibit their in vitro virus production. J. Lipid Res. 2010. 51: 286-296.7
- Adori M, Kiss E, Barad Zs, Barabas K, Kiszely E, Schneider A, Sziksz E, Abraham I, Matko J, Sarmay G: Estrogen augments the T cell-dependent but not the T-independent immune response. Cell. Mol. Life Sci. 2010. 67:1661-1674.
- Izsepi E, Balogh A, Farkas A, Molnar A, Solymos E, Toth EA, Csepanyi-Komi R, Matko J: The AC8 IgG3 monoclonal anti-cholesterol antibody modulates uptake and presentation of antigens for T cell activation. Immunol. Letters 2012. 143:106-115.